Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes. - Publication - Bridge of Knowledge

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Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes.

Abstract

5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311), a promising antitumor agent that is also active against autoimmune diseases, was determined to be a selective inhibitor of the cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes. Therefore, C-1311 might modulate the effectiveness of other drugs used in multidrug therapy. The present work aimed to identify the mechanism of the observed C-1311-mediated inactivation of CYP1A2 and CYP3A4. The inactivation experiments were performed in vitro using the human recombinant CYP1A2 and CYP3A4 (Bactosomes). CYP isoenzyme activities were determined using the CYP-specific reactions, 7-ethoxycoumarin O-deethylation (CYP1A2) and testosterone 6β-hydroxylation (CYP3A4). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by RP-HPLC with UV-Vis detection. The inhibition of CYPs by C-1311 was time-, concentration- and NADPH-dependent, which suggested a mechanism-based mode of action. Using a 10-fold dilution method and potassium ferricyanide we demonstrated the irreversible nature of the inhibition. In addition, the inhibition was attenuated by the presence of alternate substrates (alternative active site ligands) but not by a nucleophilic trapping agent (glutathione) or a reactive oxygen scavenger (catalase), which further supported a mechanism-based action. Substrate depletion partition ratios of 299 and 985 were calculated for the inactivation of CYP1A2 and CYP3A4, respectively. Our results indicated that C-1311 is a potent mechanism-based inactivator of CYP1A2 and CYP3A4. This finding provided new insights into the mechanism of C-1311 antitumor action, particularly in relation to potential pharmacokinetic drug–drug interactions between C-1311 and/or its derivatives and the substrates of CYP isoforms.

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DOI:
Digital Object Identifier (open in new tab) 10.1016/j.pharep.2016.02.003
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Category:
Articles
Type:
artykuł w czasopiśmie wyróżnionym w JCR
Published in:
Pharmacological Reports no. 68, edition 4, pages 663 - 670,
ISSN: 1734-1140
Language:
English
Publication year:
2016
Bibliographic description:
Potęga A., Fedejko-Kap, B., Mazerska Z.: Imidazoacridinone antitumor agent C-1311 as a selective mechanism- based inactivator of human cytochrome P450 1A2 and 3A4 isoenzymes.// Pharmacological Reports. -Vol. 68, iss. 4 (2016), s.663-670
DOI:
Digital Object Identifier (open in new tab) 10.1016/j.pharep.2016.02.003
Verified by:
Gdańsk University of Technology

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